Osmium compounds

Abstract

The present invention relates to osmium compounds of formula (I), their preparation and use in methods of treatment, particularly for cancer treatment.

1 - 27 . (canceled) 
     
     
         28 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a dinuclear or polynuclear form thereof, wherein, 
         M is an osmium (II) atom, 
         or, in said dinuclear or polynuclear forms, at least one M is an osmium (II) atom,
 Ar is an arene moiety, 
 X is halo, or a donor ligand, 
 Y———Z is a bidentate ligand, optionally linked to said arene moiety, wherein the dashed line represents a group of atoms linking Y and Z, 
 Y and Z are independently selected from O, N or S, with the proviso that Y and Z are not both O, 
 Q is an ion, and is either absent or present, 
 m and n are charges, independently either absent or selected from a positive or negative whole number, 
 or solvates or prodrugs thereof or physiologically active derivatives thereof, and excluding the compounds having the following formula: 
 
       
       
         
           
           
               
               
           
         
       
       wherein Q′ is BF 4  (compound II) or BPh 4  (compound III). 
     
     
         29 . The compound according to  claim 28 , wherein Y is N and Z is O or vice versa, and the N is a member of an aromatic ring. 
     
     
         30 . The compound according to  claim 29 , wherein the Y———Z ligand has a structure (IV): 
       
         
           
           
               
               
           
         
         wherein, the ring A is a substituted or unsubstituted aromatic ring, optionally fused to one or more aromatic or saturated or unsaturated rings, and optionally includes one or more further heteroatoms in ring A or in the rings fused therewith; 
         G is O or NR 3 , wherein R 3  is selected from the group consisting of hydrogen, branched or unbranched substituted or unsubstituted linear or cyclic alkyl, branched or unbranched substituted or unsubstituted linear or cyclic alkenyl, branched or unbranched substituted or unsubstituted linear or cyclic alkynyl or substituted or unsubstituted monocyclic or polycyclic aryl or heteroaryl; 
         R 1  and R 2  are independently selected at each occurrence from the group consisting of hydrogen, branched or unbranched substituted or unsubstituted linear or cyclic alkyl, branched or unbranched substituted or unsubstituted linear or cyclic alkenyl, branched or unbranched substituted or unsubstituted linear or cyclic alkynyl or substituted or unsubstituted monocyclic or polycyclic aryl or heteroaryl, carboxy, alkyloxycarbonyl hydroxyl, amino, nitro, alkyloxy, alkylthio, formyl, cyano, carbamoyl, halo (e.g. fluoro, chloro, bromo or iodo), —S(O)NR 12 R 13  or —S(O)R 14 , or together, independently at each occurrence, form the group ═O or ═S, or independently may combine with ring A to form a ring fused with ring A, such fused ring being saturated or unsaturated, substituted or unsubstituted with any of the above-listed groups, and optionally includes one or more further heteroatoms; 
         p is a number from 1 to 6; 
         the bond labelled a is a single bond when both R 1  and R 2  on the carbon adjacent G are present or a double bond when one of R 1  and R 2  on the carbon adjacent G is absent; and the dashed lines represent the bonds to the metal (II) atom. 
       
     
     
         31 . The compound according to  claim 30 , wherein p is 1. 
     
     
         32 . The compound according to  claim 30 , wherein G is N and R 3  is a substituted or unsubstituted phenyl ring. 
     
     
         33 . The compound according to  claim 32 , wherein R 1  and R 2  together form the group ═O. 
     
     
         34 . The compound according to  claim 30 , wherein G is O, the bond a is a double bond, one of R 1  or R 2  is absent and the other is amino substituted with a substituted or unsubstituted phenyl ring. 
     
     
         35 . The compound according to  claim 30 , wherein the aromatic ring A is a substituted or unsubstituted pyridine ring or substituted or unsubstituted naphthalene ring. 
     
     
         36 . The compound according to  claim 28 , wherein the ligand Y———Z is picolinate or 8-oxyquinoline. 
     
     
         37 . The compound according to  claim 28 , wherein Y is N, Z is N, and the dashed line is —CR 3 R 4 —CR 5 R 6 —,
 wherein R 3 , R 4 , R 5  and R 6  are independently selected at each occurrence from the group consisting of hydrogen, branched or unbranched substituted or unsubstituted linear or cyclic alkyl, branched or unbranched substituted or unsubstituted linear or cyclic alkenyl, branched or unbranched substituted or unsubstituted linear or cyclic alkynyl or substituted or unsubstituted monocyclic or polycyclic aryl or heteroaryl, carboxy, alkyloxycarbonyl hydroxyl, amino, nitro, alkyloxy, alkylthio, formyl, cyano, carbamoyl, halo (e.g. fluoro, chloro, bromo or iodo), —S(O)NR 12 R 13  or —S(O)R 14 , or together, independently at each occurrence, form the group ═O or ═S or independently may combine with one or both of the donor nitrogen atoms to form a nitrogen-containing substituted or unsubstituted aliphatic or aromatic ring, wherein R 13  and R 14  are independently selected from H, branched or unbranched substituted or unsubstituted linear or cyclic alkyl, branched or unbranched substituted or unsubstituted linear or cyclic alkenyl, branched or unbranched substituted or unsubstituted linear or cyclic alkynyl, or substituted or unsubstituted monocyclic or polycyclic aryl or heteroaryl.   
     
     
         38 . The compound according to  claim 37 , wherein R 3 , R 4 , R 5  and R 6  are each hydrogen. 
     
     
         39 . The compound according to  claim 28 , wherein Y and Z are each S. 
     
     
         40 . The compound according to  claim 28 , wherein Ar is selected from the group consisting of substituted or unsubstituted benzene, naphthalene, anthracene, phenanthrene, fluoranthene, pyrene, triphenylene, fluorene, indene, biphenyl, cumene, styrene, mesitylene, cymene, toluene, xylene, dihydronaphthalene (C 10 H 10 ), tetradecahydroanthracene, 6,7-dihydro-5H-benzocyclo-heptane and the like. 
     
     
         41 . The compound according to  claim 35 , wherein Ar is cymene or biphenyl. 
     
     
         42 . The compound according to claim  1 , wherein X is chloro. 
     
     
         43 . The compound according to  claim 28 , wherein Q is a negatively charged ion selected from the group consisting of BF 4 , BPh 4 , PF 6 , triflate and halides. 
     
     
         44 . A method of preparing a compound according to formula (I): 
       
         
           
           
               
               
           
         
         or a dinuclear or polynuclear form thereof, wherein, 
         M is an osmium (II) atom, or, in said dinuclear or polynuclear forms, at least one M is an osmium (II) atom, 
         Ar is an arene moiety, 
         X is halo, or a donor ligand, 
         Y———Z is a bidentate ligand, optionally linked to said arene moiety, wherein the dashed line represents a group of atoms linking Y and Z, 
         Y and Z are independently selected from O, N or S, with the proviso that Y and Z are not both O, 
         Q is an ion, and is either absent or present, 
         m and n are charges, independently either absent or selected from a positive or negative whole number, or solvates or prodrugs thereof or physiologically active derivatives thereof, 
         the method comprising providing a compound of formula ArOsX 2  in a first step and then reacting the compound with a ligand Y———Z in a second step to provide a compound according to formula (I). 
       
     
     
         45 . A pharmaceutical composition comprising a compound according to  claim 28 , without excluding the compounds (II) and (III), together with a pharmaceutically acceptable carrier therefor. 
     
     
         46 . A method of treatment or prophylaxis of a disease involving cell proliferation, said method comprising administering a therapeutically or prophylactically useful amount of a compound according to claim  1 , without excluding the compounds (II) and (III), to a subject in need thereof. 
     
     
         47 . The method according to  claim 46 , wherein the disease is cancer. 
     
     
         48 . The method according to  claim 47 , wherein the cancer is selected from the group consisting of a carcinoma, a hematopoietic tumour of lymphoid lineage, a hematopoietic tumor of myeloid lineage, thyroid follicular cancer, a tumour of mesenchymal origin, a tumor of the central or peripheral nervous system, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentoum, keratoctanthoma, thyroid follicular cancer or Kaposi's sarcoma. 
     
     
         49 . The method according to  claim 46 , wherein the compound according to formula (I) is administered together with one or more further therapeutic agents selected from the group consisting of topoisomerase inhibitors, alkylating agents, antimetabolites, DNA binders and microtubule inhibitors, or a therapeutic treatment. 
     
     
         50 . The method according to  claim 49 , wherein the further therapeutic agent or the therapeutic treatment is selected from the group consisting of cisplatin, cyclophosphamide, doxorubicin, irinotecan, fludarabine, 5FU, taxanes, mitomycin C or radiotherapy.